1. Field of the Invention
This invention relates to microporous membranes and more particularly to modified nylon membrane having a relatively low binding capacity for protein and which is suitable for the filtration of aqueous fluids, such as biological liquids containing proteins.
2. Prior Art
Microporous membranes are well known in the art. For example, U.S. Pat. No. 3,876,738 to Marinaccio, et al. (1975) describes a process for preparing a microporous membrane, for example, by quenching a solution of a film forming polymer in a non-solvent system for the polymer. European patent application No. 0 005 536 to Pall (1979) describes a similar process.
Commercially available microporous membranes, for example, made of nylon, are available from Pall Corporation, Glen Cove, N.Y. under the trademark ULTIPOR N.sub.66. Such membranes are advertised as useful for the sterile filtration of pharmaceuticals, e.g. removal of micro- organisms.
Cationically charged membranes which are used for the filtration of anionic particulate contaminants are also known in the art. For example, charge modified filter membranes are disclosed in the Assignee's Japanese Patent No. 923649 and French Patent No. 7415733. As disclosed therein, an isotropic cellulose mixed ester membrane, was treated with a cationic colloidal melamine formaldehyde resin to provide charge functionality.
Assignee herein has also developed cationic charge modified microporous membranes for use in the filtration of fluids. These cationic membranes, their preparation and use are described in Barnes, et al. U.S. Pat. No. 4,473,475 and Ostreicher, et al. U.S. Pat. No. 4,473,474. Cationic charge modified nylon membranes covered by these inventions are now being sold by CUNO Incorporated under the trademark ZETAPOR. Pall Corp., Glen Cove, N.Y. is also selling a cationic charge modified nylon membrane under trademark N.sub.66 POSIDYNE produced by the cocasting process. See Degen, et al. U.S. Pat. 4,702,804.
Anionically charged microporous filter membrane for the removal of fine charged particulates from liquids used for crossflow filtration are also known, see Chu, et al. U.S. Pat. No. 4,604,208.
However, most of these membranes, particularly nylon membranes, to a greater or lesser degree tend to bind proteinaceous materials, e.g., BSA, IgG, during filtration of fluids containing these proteins. It is theorized that this is due to the interaction of the residual charged groups on, for example, the nylon membrane with the protein molecules. This tends to clog the membranes more rapidly, increase pressure drop and, perhaps more importantly, remove desirable proteins from the solution being filtered.
For example, the DURAPORE hydroxyl-modified poly-vinylidene fluoride (PVDF) filter from Millipore, Inc., has been advertised frequently as a membrane of highest product recovery. Millipore's studies show that nylon membrane consistently binds 50-100 times more protein per sq. cm than DURAPORE.
Pall Corporation offers a product called Bio-Inert Membrane filter which is a hydrophilic hydroxyl-modified polyamide (nylon 66) membrane. The membrane is said to be " . . . too rich in covalent-linked hydroxyl groups, which are an integral component of the membrane . . . making it inherently hydrophilic and virtually passive to adsorption of protein." (Filtration News, Pall Corp., winter 1987) This membrane is claimed to bind less than 3-5 .mu.g of protein per cm.sup.2 filter area.
European patent application Publication No. 0272842 to Pall Corp. describes a porous polymeric medium having low protein affinity. More specifically, this reference describes coating nylon 66 with a condensation reaction of (a) a polymer having a plurality of hydroxyl moieties with (b) a cross-linking agent having radicals or other moieties capable of reacting with the hydroxyl moieties on the polymer, followed by curing. Examples of (a) are cellulose derivatives, hydroxyalkyl esters of cellulose and hydroxyalkyl esters of acrylic acid and methacrylic acid, e.g. polyhydroxyethyl methacrylate, polyvinyl alcohol and starch. Examples of (b) are compounds having acidic moieties, e.g. carboxylic acid groups and phenolic groups, as well as methylol compounds, resoles, amide groups and aldehydes, copolymers of acrylic acid and acrylamide, copolymers of acrylic acid and N-methylol acrylamide and polyacrylic acid.
Hou et al U.S. Pat. Nos. 4,663,163, 4,687,820 and 4,724,207 in their preferred embodiment describe polysaccharides, polypeptides and siliceous materials modified by a polymer of a reactive monomer such as glycidyl methacrylate (GMA) or glycidyl acrylate (GA), and another functional monomer such as diethylaminoethyl methacrylate (DEAE), or .beta.-carboxy ethyl acrylate (.beta.-CEA) to obtain an ion-exchange media for molecular separation or chromatography.
Of additional interest are the following U. S. patents:
______________________________________ U.S. Pat. No. Inventor ______________________________________ 4,377,100 Fydelor et al 4,618,533 Steuck 4,634,604 Tlustakova et al 4,702,840 Degen et al 4,765,897 Cadotte et al 4,778,596 Linder et al 4,828,700 Fibiger et al ______________________________________
Degen et al U.S. Pat. No. 4,707,266 discloses polyamide membranes produced by the cocasting method which may be useful for processing biological and biochemical preparations. The membranes are prepared from a casting solution comprised of an alcohol insoluble polyamide resin and a water soluble membrane surface modifying polymer. The surface modifying polymers may include hydroxy alkyl acrylates.
Tlustakova U.S. Pat. No. 4,634,604 discloses a method for producing a biocompatible layer on the surface of particulate sorbent material. The biocompatible layer is a homopolymer or copolymer of 2-hydroxyethyl methacrylate.
Fydelor et al U.S. Pat. No. 4,377,010 discloses a biocompatible device comprising a base polymer having a surface of a graft copolymer selected from acrylic acid and alkyl substituted acrylic acids.
The remainder of the aforecited patents generally disclose separation membranes which are coated, encapsulated or surface modified with a polymeric compound. Cadotte et al U.S. Pat. No. 4,765,897 and Fibiger et al U.S. Pat. No. 4,828,700 disclose a polyamide reverse osmosis membrane which may be treated with a rejection enhancing agent which may comprise a copolymer of hydroxyethyl methacrylate with methacrylate acid.
Steuck U.S. Pat. No. 4,618,533 (Millipore Corp.) describes modifying microporous membranes which are hydrophobic to make them hydrophilic with hydroxy alkyl acrylates or methacrylates cross-linked with difunctional acrylates or methacrylates, e.g., glycidyl acrylate.
It is thus desirable to modify the surfaces, in particular the microporous microstructure, of such membranes to achieve effective removal of impurities from protein containing solutions without altering product yield, i.e. removing protein. Such a modified membrane must not have excessive extractables, the pore structure should not be altered or blocked, the modifying agent must be bio-compatible and non-toxic and the membrane's physical-mechanical properties must not be detrimentally effected by such modification.